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Inositol 3,4,5,6-tetrakisphosphate inhibits insulin granule acidification and fusogenic potential.

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Author

Summary, in English

ClC Cl(-) channels in endosomes, synaptosomes, lysosomes, and beta-cell insulin granules provide charge neutralization support for the functionally indispensable acidification of the luminal interior by electrogenic H(+)-ATPases (Jentsch, T. J., Stein, V., Weinreich, F., and Zdebik, A. A. (2002) Physiol. Rev. 82, 503-568). Regulation of ClC activity is, therefore, of widespread biological significance (Forgac, M. (1999) J. Biol. Chem. 274, 12951-12954). We now ascribe just such a regulatory function to the increases in cellular levels of inositol 3,4,5,6-tetrakisphosphate (Ins(3,4,5,6)P(4)) that inevitably accompany activation of the ubiquitous Ins(1,4,5)P(3) signaling pathway. We used confocal imaging to record insulin granule acidification in single mouse pancreatic beta-cells. Granule acidification was reduced by perfusion of single cells with 10 microm Ins(3,4,5,6)P(4) (the concentration following receptor activation), whereas at 1 microm ("resting" levels), Ins(3,4,5,6)P(4) was ineffective. This response to Ins(3,4,5,6)P(4) was not mimicked by 100 microm Ins(1,4,5,6)P(4) or by 100 microm Ins(1,3,4,5,6)P(5). Ins(3,4,5,6)P(4) did not affect granular H(+)-ATPase activity or H(+) leak, indicating that Ins(3,4,5,6)P(4) instead inhibited charge neutralization by ClC. The Ins(3,4,5,6)P(4)-mediated inhibition of vesicle acidification reduced exocytic release of insulin as determined by whole-cell capacitance recordings. This may impinge upon type 2 diabetes etiology. Regulatory control over vesicle acidification by this negative signaling pathway in other cell types should be considered.

Publishing year

2002

Language

English

Pages

26717-26720

Publication/Series

Journal of Biological Chemistry

Volume

277

Issue

30

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Endocrinology and Diabetes

Keywords

  • Secretory Vesicles : drug effects
  • Signal Transduction
  • Chlorides : metabolism
  • Non-U.S. Gov't
  • Support
  • Cultured
  • Chloride Channels : metabolism
  • Animal
  • Microscopy
  • Confocal
  • Islets of Langerhans : metabolism
  • Mice
  • Insulin : metabolism
  • Cells
  • Inositol Phosphates : pharmacology

Status

Published

Research group

  • Diabetes - Islet Patophysiology

ISBN/ISSN/Other

  • ISSN: 1083-351X